The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Aprepitant (5-([(2R,3S)-2-((R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluoro-phenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one) is an antiemetic compound that belongs to the class of substance P antagonists that mediate their effect by blocking the neurokinin (NK1) receptor. Aprepitant is a selective, high-affinity antagonist at human substance P NK-1 receptors and is manufactured by Merck & Co. (available under the brand name, Emend®). It is available as solid capsules (40, 80 and 125 mg) or powder (115 and 150 mg) for injection for the prevention and control of acute and delayed chemotherapy induced nausea and vomiting, and for prevention of postoperative nausea and vomiting. The recommended dose of EMEND capsules is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3 and also indicated for the postoperative nausea and vomiting (PONV) 40 mg within 3 hours prior to induction of anesthesia.
Following oral administration of a single 40 mg dose of EMEND in the fasted state, mean area under the plasma concentration-time curve (AUCo-∞) was 7.8 mcg/hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg mL, occurring at approximately 3 hours post-dose (tmax). The absolute bioavailability at the 40-mg dose has not been determined. Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUCo-24 hr was approximately 19.6 mcg*hr/mL and 21.2 mcg*hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80-125 mg, the mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.
Unfortunately, oral capsule formulations may not be easy to swallow for patients after chemotherapy or postoperative condition as such capsules often induce nausea and vomiting, and there are no liquid formulation of aprepitant commercially available. In an alternative described elsewhere (Secundum Artem; Current & Practical Compounding Information for the Pharmacist. Perrigo Pharmaceuticals (Volume 16 Number 1)), an aprepitant oral suspension can be prepared at the point of use by grinding a 125 mg capsule and combining the ground powder with Ora-Blend™ (gum-based fluid, commercially available from Paddock laboratories). Here, contents of an aprepitant capsule were emptied into a mortar and ground to a fine powder. A small amount of Ora-Blend® was added to the fine powder and triturated to a smooth paste. More Ora-Blend was added and the mixture transferred to a graduate. The mortar was rinsed with Ora-Blend and the mixture added to the graduate. Finally, sufficient Ora-Blend was added to final volume and mixed well. Unfortunately, such preparations are not stable and will generally not achieve a uniform suspension, which may affect bioavailability.
Such and other difficulties in preparing aprepitant solutions are well known in the art and are described, for example, in US 2009/0209541 and US 2011/0009362, particularly as they relate to solubility of aprepitant. All publications identified herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. Similarly, WO 03/049718 addresses various issues associated with poor delivery characteristics of aprepitant. Here, nanoparticulate compositions of aprepitant are disclosed with stabilizers adsorbed on its surface to maintain an effective average particle size of less than about 1000 nm. On the other hand, US 2014/0272100 teaches coatings of carrier particles with aprepitant microparticles, and WO 2008/104512 describes different polymorphs in an attempt to increase solubility. However, all or almost all of compositions fail to provide a premade liquid formulation that is stable over a prolonged time, particularly where suspensions are prepared. Among other difficulties, the particles in the suspensions tend to agglomerate over time and precipitate out of solution and/or become less bioavailable due to increase in size.
Therefore, even though numerous liquid formulations for aprepitant are known in the art, all or almost all of them suffer from one or more disadvantage. Thus, there is still a need to provide improved oral liquid aprepitant formulations that have aprepitant particles in suspension for extended time without agglomeration and concomitant precipitation.